Salts of aza-bicyclic di-aryl ethers and methods to make them or their precursors

Abstract

The present invention relates to salts of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, to methods for making them or their precursors, to pharmaceutical compositions comprising them, and to their use as medicaments.

The invention claimed is: 
     
       1. A process for the production of a compound of formula I 
       
         
           
           
               
               
           
         
       
       or a salt thereof, the process comprising:
 reacting a compound of formula II 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof, with a compound of formula V 
       
         
           
           
               
               
           
         
       
       or a salt thereof, at elevated temperature in the presence of a base and an inert dipolar aprotic solvent,
 wherein the base is (M 2 )OC(R) 3 , wherein M 2  is sodium or potassium and each R independently is C 1-6 alkyl or two R together with the carbon atom they are bound to form C 4-6  cycloalkyl, or the base is a hydroxide base, 
 to form the compound of formula I; and 
 optionally converting the compound of formula Ito a salt thereof. 
 
     
     
       2. The process according to  claim 1 , wherein the base is gradually added to the reaction mixture. 
     
     
       3. The process according to  claim 1 , wherein the base is sodium tert-butanolate or potassium tert-butanolate. 
     
     
       4. The process according to  claim 1 , wherein the inert dipolar aprotic solvent is dimethylsulfoxide. 
     
     
       5. The process according to  claim 4 , wherein the reaction mixture further comprises toluene. 
     
     
       6. The process according to  claim 1 , further comprising producing the compound of formula II or the salt thereof 
       
         
           
           
               
               
           
         
       
       according to a process comprising:
 a) reacting a compound of formula III 
 
       
         
           
           
               
               
           
         
       
       with a compound of formula IV 
       
         
           
           
               
               
           
         
       
       and/or with a compound of formula IVA 
       
         
           
           
               
               
           
         
       
       wherein M 1  is alkali and n is 1, or M 1  is earth alkali and n is 2; 
       in the presence of a palladium catalyst; a base selected from a carbonate base, a phosphate base, a hydroxide base, and an alcoholate base; water and an inert solvent; 
       to form the compound of formula II; and
 b) optionally converting the compound of formula II to a salt thereof. 
 
     
     
       7. The process according to  claim 6 , wherein the reaction of the compound of formula III with the compound of formula IV and/or the compound of formula IVA is carried out at a pH from 10.5 to 13. 
     
     
       8. The process according to  claim 6 ,
 wherein the inert solvent is a partly water soluble solvent; 
 wherein cysteine is added to the biphasic reaction mixture after formation of the compound of formula II; the phases are separated; and the compound of formula II is isolated from the non-aqueous phase.